Submissions for variant NM_018100.4(EFHC1):c.817G>T (p.Val273Leu)

gnomAD frequency: 0.00012  dbSNP: rs369926953

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187348	SCV000240933	uncertain significance	not provided	2014-09-18	criteria provided, single submitter	clinical testing	p.Val273Leu (GTG>TTG): c.817 G>T in exon 5 of the EFHC1 gene (NM_018100.3). The V273L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V273L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV003765176	SCV000763152	uncertain significance	Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1	2022-09-19	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EFHC1 protein function. ClinVar contains an entry for this variant (Variation ID: 205391). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. This variant is present in population databases (rs369926953, gnomAD 0.03%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 273 of the EFHC1 protein (p.Val273Leu).
GenomeConnect, ClinGen	RCV000509213	SCV000607051	not provided	Juvenile myoclonic epilepsy		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.